26 March 2006: DURHAM, N.C. -- A single nutrient found in soy products elicits changes in gene behavior that permanently reduce an embryo's risk of becoming obese later in life, according to an animal study at Duke University Medical Center.

The findings, yet to be confirmed in humans, could explain why Asians have lower rates of obesity and cancer, said the Duke researchers. Asians consume large amounts of soy, which has been linked to lower rates of breast, endometrial and prostate cancer, among other health benefits.

In the Duke study, pregnant Agouti mice that ate a diet rich in genistein, an active ingredient in soy, gave birth to pups that stayed slimmer as adults. Mice that did not receive genistein in utero were much heavier as adults — double the weight of their genistein-fed counterparts. Prenatal genistein also shifted the offspring's coat color from yellow to brown, demonstrating that a single nutrient can have a widespread systemic impact, said the researchers.

Genistein's effect occurred early in pregnancy, the equivalent of eight gestational days in humans. The Duke scientists said their results lend support to the "developmental origins of adult disease" hypothesis, in which an individual's long-term health is influenced by prenatal factors.

Results of the study, funded by the National Institute of Environmental Health Sciences and the National Cancer Institute, are published in the April 1, 2006, issue of the journal Environmental Health Perspectives.

"We are increasingly finding that our parent's and even our grandparent's nutritional status and environmental exposures can regulate our future risk of disease," said Randy Jirtle, Ph.D., professor of radiation oncology and senior author of the study. "In other words, it may not only be the hamburgers and fries we are eating, but also what our parents consumed or encountered in the environment that predisposes us to various conditions."

Jirtle said a mechanism called DNA "methylation" is increasingly identified as the trigger for environmentally-caused gene alterations. During this process, a person's exposure to chemicals, nutrients, or even a behavioral experience such as nurturing can elicit a change in how a specific gene behaves — but without altering the genetic sequence in any way.

Rather, the exposure or event prompts a quartet of atoms or "methyl group" to attach to the regulatory region of a gene, where it acts as a switch to activate or silence the gene. Such an effect is called "epigenetic" because it occurs over and above the gene sequence without altering any of the letters of the gene's four-unit code, said Jirtle. Micronutrients can change the extent of DNA methylation by directly donating methyl groups or by altering the efficiency by which DNA methylation is modified, said Jirtle.

In the current study, maternal dietary genistein caused a single mouse gene called "agouti" to become methylated at six specific sites near its regulatory region, thereby reducing the gene's expression. The agouti methylation consistently occurred throughout several germ layers of embryonic tissue, indicating that genistein acted during early embryonic development. Moreover, the methylation changes persisted into adulthood, providing the first evidence that in utero dietary genistein alters epigenetic gene regulation, coat color, and susceptibility to adult obesity in animals.

The agouti gene is not epigentically regulated in humans as it is in the Agouti mouse, said Jirtle. But soy's potential benefits could exert themselves through other human genes whose expression is altered by DNA methylation, he said.

"Methylation is a common event in the human genome, and it is a highly malleable effect that occurs during rapid periods of development, but it can also occur in childhood and even in adulthood," he said.

Because many infants receive soy milk, the impact of genistein in humans should be carefully assessed, he said. Pregnant women are exposed to hundreds of compounds in foods, prenatal vitamins and the environment that could potentially methylate susceptible genes, he said. The effects of each compound could be beneficial or detrimental, depending upon the timing of exposure, the dose and the tissue exposed, said Jirtle.

"Our study demonstrates there are highly sensitive windows early in development when environmental exposures can permanently alter the offspring's adult susceptibility to disease," said Jirtle. "Therefore, we need to examine the effect of environmental exposures during pregnancy, not just in adulthood, if we want to accurately assess their risk or benefit to humans."

His earlier research demonstrated that four common nutritional supplements fed to pregnant mice, including folic acid and vitamin B12, lowered their offspring's susceptibility to obesity, diabetes and cancer by methylating the same agouti gene. Yet how nutrients interact in combination or in extremely high doses remains unclear, he said.

"There could be additive or synergistic effects between folic acid and genistein, or any such compounds, that hypermethylate certain genes," said Dana Dolinoy, MPH, lead author of the study. "What is good in small amounts could be harmful in large amounts. We simply don't know the effects of literally hundreds of compounds that we intentionally or inadvertently ingest or encounter each day."

Of related concern, soy is a staple of almost all laboratory mouse diets. Soy could inadvertently methylate select genes and thus mask the deleterious effects of various chemicals being tested for their risk in humans, she said.

"In the future, we may be able to potentially select compounds to protect a person from being predisposed to developing a variety of conditions," said Jirtle. "There is a vast, unknown potential for studying how our environment interacts with our epigenome to determine how we developed and who we will become."